The HLA-DRB1 gene, part of the Human Leukocyte Antigen (HLA) class II complex on chromosome 6. encodes cell surface proteins critical for immune regulation. These molecules present antigenic peptides to CD4+ T-cells, initiating adaptive immune responses. HLA-DRB1 exhibits high polymorphism, with over 1.500 alleles identified, influencing disease susceptibility and transplant compatibility. Antibodies targeting HLA-DRB1 arise from sensitization events like blood transfusions, pregnancies, or prior transplants. In transplantation, donor-specific anti-HLA-DRB1 antibodies are associated with antibody-mediated rejection (AMR) and graft failure, necessitating pre-transplant crossmatching and desensitization protocols. Clinically, these antibodies are detected via solid-phase assays like single-antigen bead arrays. Beyond transplantation, HLA-DRB1 antibodies are linked to autoimmune disorders. For instance, certain HLA-DRB1 alleles (e.g., *04:01. *04:04) correlate with rheumatoid arthritis risk, where anti-citrullinated protein antibodies (ACPAs) may cross-react with HLA-DRB1 epitopes. Research also explores their role in conditions like lupus and sarcoidosis. Therapeutic strategies focus on reducing antibody titers (plasmapheresis, IVIG) or blocking effector mechanisms (complement inhibitors). Emerging studies investigate epitope-specific targeting to improve HLA matching and personalize immunosuppression. Understanding HLA-DRB1 antibody dynamics remains vital for advancing transplant outcomes and unraveling autoimmune pathogenesis.